Impact of co-mutations and transcriptional signatures in non-small cell lung cancer patients treated with adagrasib in the KRYSTAL-1 trial.

Background: KRAS inhibitors are revolutionizing the treatment of NSCLC, but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Methods: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib (KRYSTAL-1-NCT03785249) were included in the analysis. Pre-treatment NGS data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free and overall survival. KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1MUT and STK11MUT were associated with shorter survival to adagrasib (KEAP1: PFS 4.1m vs 9.9m, HR 2.7, p<0.01; OS 5.4m vs 19.0m, HR 3.6, p<0.01; STK11: PFS 4.2m vs 11.0m, HR 2.2, p<0.01; OS 9.8m vs NR, HR 2.6, p<0.01). KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9m) and OS (NR). Pre-clinical analyses further validate the association between KEAP1 loss-of-function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2m vs 8.4m, HR 2.0, p=0.02; OS: 6.5m vs 19.0m, HR 2.8, p<0.01) even in KEAP1WTNSCLC patients. KEAP1WT/STK11WT/NRF2LOW status identified patients - 32% - with longer survival to adagrasib (PFS 12.0m vs 4.2m, HR 0.2, p<0.01; OS NR vs 8.0m, HR 0.1, p<0.01).

Conclusions: KEAP1, STK11 and NRF2 status define KRASG12C-mutant NSCLC patients with markedly distinct outcomes to adagrasib. These results further support the use of genomic features - mutational and non-mutational - for treatment selection of KRASG12C-mutant NSCLC patients.